tbuckley/cabot-search huggingface dataset:
Race and Ethnicity Stratification for Polygenic Risk Score Analyses May Mask Disparities in Hispanics
Authors: Shoa L. Clarke, Rose D.L. Huang, Austin T. Hilliard, Catherine Tcheandjieu, Julie Lynch, Scott M. Damrauer, Kyong-Mi Chang, Philip S. Tsao, Themistocles L. Assimes
Journal: Circulation (2022)
Elevated Retinol Binding Protein 3 Concentrations Are Associated With Decreased Vitreous Inflammatory Cytokines, VEGF, and Progression of Diabetic Retinopathy
Authors: Ward Fickweiler, Hyunseok Park, Kyoungmin Park, Margalit G. Mitzner, Tanvi Chokshi, Tahani Boumenna, John Gautier, Yumi Zaitsu, I-Hsien Wu, Jerry Cavallerano, Lloyd P. Aiello, Jennifer K. Sun, George L. King
Journal: Diabetes Care (2022)

To correlate inflammatory cytokines and vascular endothelial growth factor (VEGF) in vitreous and plasma with vitreous retinol binding protein 3 (RBP3), diabetic retinopathy (DR) severity, and DR worsening in a population with type 1 and type 2 diabetes.RBP3, VEGF, and inflammatory cytokines were measured in plasma and vitreous samples (n = 205) from subjects of the Joslin Medalist Study and Beetham Eye Institute.Higher vitreous RBP3 concentrations were associated with less severe DR (P < 0.0001) and a reduced risk of developing proliferative DR (PDR) (P < 0.0001). Higher RBP3 correlated with increased photoreceptor segment thickness and lower vitreous interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and TNF-β (P < 0.05). PDR was associated with lower vitreous interferon-γ and IL-10 and higher VEGF, IL-6, and IL-15 (P < 0.05), but was not associated with their plasma concentrations.Higher vitreous RBP3 concentrations are associated with less severe DR and slower rates of progression to PDR, supporting its potential as a biomarker and therapeutic agent for preventing DR worsening, possibly by lowering retinal VEGF and inflammatory cytokines.
Drugs in Clinical Development to Treat Autosomal Dominant Polycystic Kidney Disease
Authors: Thomas Bais, Ron T. Gansevoort, Esther Meijer
Journal: Drugs (2022)

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation that ultimately leads to kidney failure in most patients. Approximately 10% of patients who receive kidney replacement therapy suffer from ADPKD. To date, a vasopressin V2 receptor antagonist (V2RA) is the only drug that has been proven to attenuate disease progression. However, aquaresis-related adverse events limit its widespread use. Data on the renoprotective effects of somatostatin analogues differ largely between studies and medications. This review discusses new drugs that are investigated in clinical trials to treat ADPKD, such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators and micro RNA inhibitors, and drugs already marketed for other indications that are being investigated for off-label use in ADPKD, such as metformin. In addition, potential methods to improve the tolerability of V2RAs are discussed, as well as methods to select patients with (likely) rapid disease progression and issues regarding the translation of preclinical data into clinical practice. Since ADPKD is a complex disease with a high degree of interindividual heterogeneity, and the mechanisms involved in cyst growth also have important functions in various physiological processes, it may prove difficult to develop drugs that target cyst growth without causing major adverse events. This is especially important since long-standing treatment is necessary in this chronic disease. This review therefore also discusses approaches to targeted therapy to minimize systemic side effects. Hopefully, these developments will advance the treatment of ADPKD.
A systematic review of healthcare provider-targeted mobile applications for non-communicable diseases in low- and middle-income countries
Authors: Pascal Geldsetzer, Sergio Flores, Grace Wang, Blanca Flores, Abu Bakarr Rogers, Aditi Bunker, Andrew Y. Chang, Rebecca Tisdale
Journal: npj Digital Medicine (2022)

Abstract Mobile health (mHealth) interventions hold promise for addressing the epidemic of noncommunicable diseases (NCDs) in low- and middle-income countries (LMICs) by assisting healthcare providers managing these disorders in low-resource settings. We aimed to systematically identify and assess provider-facing mHealth applications used to screen for, diagnose, or monitor NCDs in LMICs. In this systematic review, we searched the indexing databases of PubMed, Web of Science, and Cochrane Central for studies published between January 2007 and October 2019. We included studies of technologies that were: (i) mobile phone- or tablet-based, (ii) able to screen for, diagnose, or monitor an NCD of public health importance in LMICs, and (iii) targeting health professionals as users. We extracted disease type, intervention purpose, target population, study population, sample size, study methodology, technology stage, country of development, operating system, and cost. Our initial search retrieved 13,262 studies, 315 of which met inclusion criteria and were analyzed. Cardiology was the most common clinical domain of the technologies evaluated, with 89 publications. mHealth innovations were predominantly developed using Apple’s iOS operating system. Cost data were provided in only 50 studies, but most technologies for which this information was available cost less than 20 USD. Only 24 innovations targeted the ten NCDs responsible for the greatest number of disability-adjusted life years lost globally. Most publications evaluated products created in high-income countries. Reported mHealth technologies are well-developed, but their implementation in LMICs faces operating system incompatibility and a relative neglect of NCDs causing the greatest disease burden.
Temporal Control of Trained Immunity via Encapsulated Release of <i>β</i>‐Glucan Improves Therapeutic Applications
Authors: Jainu Ajit, Britteny Cassaidy, Sophia Tang, Ani Solanki, Qing Chen, Jingjing Shen, Aaron P. Esser Kahn
Journal: Advanced Healthcare Materials (2022)

Emerging diseases require generating new vaccines, which can often be time consuming. An alternate method to boost host defense is by inducing nonspecific innate immune memory, called trained immunity, to develop novel prophylactics. Many molecules, most notably β-glucan, induce trained immunity, but their effects are often short-lived and uncontrolled. This lack of temporal control limits both the therapeutic ability of training and provides fundamental questions about its nature. To achieve temporal control of trained immunity, controlled release nanoparticles encapsulating only 3.5% of the standard dose of β-glucan to attain sustained release over a month are engineered. Nanoparticle-trained mice exhibit prolonged training effects and improve resistance to a B16F10 tumor challenge compared to mice that receive an equivalent amount of free β-glucan. The duration of trained immunity is further fine tuned by synthesizing nanoparticles composed of different molecular weights to modulate the release kinetics. These results demonstrate that dosing and temporal control can substantially alter the trained response to unanticipated levels. As such, this approach using sustained release platforms might lead to a novel prophylactic strategy for improved disease resistance against a wide variety of diseases.
Analysis of Prenatal Exposure to Opioid Analgesics and Scholastic Skills in Children in Fifth Grade in Norway
Authors: Johanne Naper Trønnes, Angela Lupattelli, Eivind Ystrom, Hedvig Nordeng
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Few studies have examined the neurodevelopmental consequences of prenatal exposure to opioid analgesics. Therefore, it is necessary to gain knowledge to inform clinical decisions for pregnant women with moderate to severe pain. <h3>Objective</h3> To investigate fifth-grade scholastic skills in children with prenatal exposure to opioid analgesics. <h3>Design, Setting, and Participants</h3> A cohort study was conducted based on data from the Norwegian Mother, Father, and Child Cohort (1999-2008). These data were linked to the Medical Birth Registry of Norway, and data from Statistics Norway included 64 256 live-born singletons, born to 54 568 mothers who reported pain during pregnancy, were analyzed. The study was conducted from July 1 to December 15, 2021. <h3>Exposures</h3> Self-reported exposure to opioid analgesics during pregnancy, characterized in terms of any exposure, the exposure timing, and the exposure duration. <h3>Main Outcomes and Measures</h3> Scores from 3 national tests for children in fifth grade. The tests measured scholastic skills in literacy, numeracy, and the English language. Test scores were standardized to<i>z</i>scores. Differences in z scores were compared between children of mothers exposed to opioid analgesics during pregnancy and children of mothers with only prepregnancy opioid exposure. <h3>Results</h3> Of the 64 256 children included, 32 521 were boys (50.6%), and 1483 children (2.3%) were exposed to an opioid analgesic at least once during gestation. All test scores were similar between children with any exposure to opioid analgesics in utero and children with only prepregnancy exposure. Children exposed in the first trimester and those exposed in two or three 4-week intervals during pregnancy scored lower than children of mothers with only prepregnancy exposures on tests in literacy (weighted β [wβ], −0.13; 95% CI, −0.25 to −0.01 and wβ, −0.19; 95% CI, −0.35 to −0.04) and numeracy (wβ, −0.14; 95% CI, −0.25 to −0.04 and wβ, −0.19; 95% CI, −0.34 to −0.05). These differences were small and may not be clinically relevant. <h3>Conclusions and Relevance</h3> In this large birth cohort, prenatal exposure to opioid analgesics had no substantial negative association with fifth-grade scholastic skills. However, adequate pain management in pregnancy may be addressed on an individual patient level, bearing in mind the benefits and risks of different analgesic therapies.
Regulatory T cells and immunoglobulin E: A new therapeutic link for autoimmunity?
Authors: Oscar Palomares, Dirk Elewaut, Peter M. Irving, Xavier Jaumont, Paolo Tassinari
Journal: Allergy (2022)

Abstract Autoimmune diseases have a prevalence of approximately 7 to 9% and are classified as either organ‐specific diseases, including type I diabetes, multiple sclerosis, inflammatory bowel disease and myasthenia gravis, or systemic diseases, including systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. While many advancements have been made in understanding of the mechanisms of autoimmune disease, including the nature of self‐tolerance and its breakdown, there remain unmet needs in terms of effective and highly targeted treatments. T regulatory cells (Tregs) are key mediators of peripheral tolerance and are implicated in many autoimmune diseases, either as a result of reduced numbers or altered function. Tregs may be broadly divided into those generated in the thymus (tTregs) and those generated in the periphery (pTregs). Tregs target many different immune cell subsets and tissues to suppress excessive inflammation and to support tissue repair and homeostasis: there is a fine balance between Treg cell stability and the plasticity that is required to adjust Tregs' regulatory purposes to particular immune responses. The central role of immunoglobulin E (IgE) in allergic disease is well recognized, and it is becoming increasingly apparent that this immunoglobulin also has a wider role encompassing other diseases including autoimmune disease. Anti‐IgE treatment restores the capacity of plasmacytoid dendritic cells (pDCs) impaired by IgE‐ high‐affinity IgE receptor (FcεR1) cross‐linking to induce Tregs in vitro in atopic patients. The finding that anti‐IgE therapy restores Treg cell homeostasis, and that this mechanism is associated with clinical improvement in asthma and chronic spontaneous urticaria suggests that anti‐IgE therapy may also have a potential role in the treatment of autoimmune diseases in which Tregs are involved.
First Genotype–Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease
Authors: Matina Prapa, Mauro Lago-Docampo, Emilia M. Swietlik, David Montani, Mélanie Eyries, Marc Humbert, Carrie L. Welch, Wendy K. Chung, Rolf M. F. Berger, Harm Jan Bogaard, Olivier Danhaive, Pilar Escribano-Subías, Henning Gall, Barbara Girerd, Ignacio Hernandez-Gonzalez, Simon Holden, David Hunt, Samara M. A. Jansen, Wilhelmina Kerstjens-Frederikse, David G. Kiely, Pablo Lapunzina, John McDermott, Shahin Moledina, Joanna Pepke-Zaba, Gary J. Polwarth, Gwen Schotte, Jair Tenorio-Castaño, A. A. Roger Thompson, John Wharton, Stephen J. Wort, Karyn Megy, Rutendo Mapeta, Carmen M. Treacy, Jennifer M. Martin, Wei Li, Andrew J. Swift, Paul D. Upton, Nicholas W. Morrell, Stefan Gräf, Diana Valverde
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype–phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype–phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource–Rare Diseases. Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.
Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma
Authors: Sarah Gooding, Naser Ansari-Pour, Mohammad Kazeroun, Kubra Karagoz, Ann Polonskaia, Mirian Salazar, Evie Fitzsimons, Korsuk Sirinukunwattana, Selina Chavda, Maria Ortiz Estevez, Fadi Towfic, Erin Flynt, William Pierceall, Daniel Royston, Kwee Yong, Karthik Ramasamy, Paresh Vyas, Anjan Thakurta
Journal: Blood (2022)

The acquisition of a multidrug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the cereblon (CRBN) protein include widely used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs. Here, we investigate alternative genomic associations of IMiD resistance, using large whole-genome sequencing patient datasets (n = 522 cases) at newly diagnosed, lenalidomide (LEN)-refractory and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory timepoints. Selecting gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of genetic disruption by mutation associated with IMiD resistance. However, we identified a chromosome region, 2q37, containing COP9 signalosome members COPS7B and COPS8, copy loss of which significantly enriches between newly diagnosed (incidence 5.5%), LEN-refractory (10.0%), and LEN-then-POM-refractory states (16.4%), and may adversely affect outcomes when clonal fraction is high. In a separate dataset (50 patients) with sequential samples taken throughout treatment, we identified acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure. The COP9 signalosome is essential for maintenance of the CUL4-DDB1-CRBN E3 ubiquitin ligase. This region may represent a novel marker of IMiD resistance with clinical utility.
Updated Malaria Recommendations for Children and Pregnant People
Authors: Howard D. Larkin
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
An optimized bicistronic chimeric antigen receptor against GPC2 or CD276 overcomes heterogeneous expression in neuroblastoma
Authors: Meijie Tian, Adam T. Cheuk, Jun S. Wei, Abdalla Abdelmaksoud, Hsien-Chao Chou, David Milewski, Michael C. Kelly, Young K. Song, Christopher M. Dower, Nan Li, Haiying Qin, Yong Yean Kim, Jerry T. Wu, Xinyu Wen, Mehdi Benzaoui, Katherine E. Masih, Xiaolin Wu, Zhongmei Zhang, Sherif Badr, Naomi Taylor, Brad St. Croix, Mitchell Ho, Javed Khan
Journal: Journal of Clinical Investigation (2022)

Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs), limited T cell persistence, and T cell exhaustion. Here, we aimed to identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed in neuroblastoma (NB), a lethal extracranial solid tumor of childhood. First, we examined CAR T cell expansion in the presence of targets by digital droplet PCR. Next, using pooled competitive optimization of CAR by cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), termed P-COCC, we simultaneously analyzed protein and transcriptome expression of CAR T cells to identify high-activity CARs. Finally, we performed cytotoxicity assays to identify the most effective CAR against each target and combined the CARs into a bicistronic "OR" CAR (BiCisCAR). BiCisCAR T cells effectively eliminated tumor cells expressing GPC2 or CD276. Furthermore, the BiCisCAR T cells demonstrated prolonged persistence and resistance to exhaustion when compared with CARs targeting a single antigen. This study illustrated that targeting multiple TAAs with BiCisCAR may overcome heterogenous expression of target antigens in solid tumors and identified a potent, clinically relevant CAR against NB. Moreover, our multimodal approach integrating competitive expansion, P-COCC, and cytotoxicity assays is an effective strategy to identify potent CARs among a pool of candidates.
Smallpox
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal